C. Mary et al., Dysregulated expression of the Cd22 gene as a result of a short interspersed nucleotide element insertion in Cd22(a) lupus-prone mice, J IMMUNOL, 165(6), 2000, pp. 2987-2996
The Cd22 gene encodes a B cell-specific adhesion molecule that modulates B
cell Ag receptor-mediated signal transduction, and is allelic to a lupus-su
sceptibility locus in New Zealand White (NZW) mice. In this study, we show
that, in addition to the wild-type transcripts, NZW (Cd22(a)) mice synthesi
ze aberrant CD22 mRNAs that contain similar to 20-120 nucleotide insertions
upstream of the coding region between exons 2 and 3, and/or similar to 100
-190 nucleotide deletions of exon 4, Sequence analysis revealed that these
aberrant mRNA species arose by alternative splicing due to the presence in
the NZW strain of a 794-bp sequence insertion in the second intron, contain
ing a fluster of short interspersed nucleotide elements. Both the presence
of sequence insertion and aberrantly spliced mRNAs were specific to mice be
aring the Cd22(a) and Cd22(c) alleles, Up-regulation of CD22 expression aft
er LPS activation appeared impaired in Cd22(a) spleen cells (twice lower th
an in Cd22(b) B cells). Furthermore, we show that partial CD22 deficiency,
i.e., heterozygous level of CD22 expression, markedly promotes the producti
on of IgG anti-DNA autoantibodies in C57BL/6 (Cd22(b)) mice bearing the Y c
hromosome-linked autoimmune acceleration gene, Yaa, Taken together, these r
esults suggest that a lower up-regulation of CD22 on activated B cells (res
ulting from Cd22 gene anomaly in Cd22(a) mice or from CD22 heterozygosity i
n mutants obtained by gene targeting) is implicated in autoantibody product
ion, providing support for Cd22(a) as a possible candidate allele contribut
ing to lupus susceptibility.